Deafness, Autosomal Recessive 77 (DFNB77) via the LOXHD1 Gene

Autosomal recessive deafness 77 (DFNB77) is characterized by moderate to profound, progressive, postlingual nonsyndromic hearing loss. The audioprofile of most nonsyndromic hearing loss cases can be distinct, thus assisting in the development of an evaluation strategy for molecular genetic testing and in generating a prognosis on the rate of hearing loss per year (Hildebrand et al. 2008). Individuals with DFNB77 generally have intact low-frequency hearing and mild to moderate mid-frequency (500-2,000 Hz) and high-frequency (>2,000 Hz) hearing loss (Grillet al. 2009). The onset of disease occurs at 7-8 years of age, progressing to moderate to profound hearing loss during adulthood. Affected individuals have normal vestibular function, thus achieving age-appropriate developmental milestones such as sitting and walking, without issues of tinnitus, balance disorders, or vertigo.

DFNB77 is an autosomal recessive hearing disorder that is caused by pathogenic sequence variants in the lipoxygenase homology domain-containing 1 (LOXHD1) gene, which is mainly expressed in the cochlear and vestibular hair cells of the inner ear, particularly along the length of stereocilia (Grillet et al. 2009). The LOXHD1 gene is located in chromosome 18q12-q21 and consists of 40 coding exons that encode a 2,211-amino acid protein (Riazuddin et al. 2012). The LOXHD1 protein consists of 15 polycystin/lipoxygenase/alpha-toxin domains, which are 120-amino acid regions that are postulated to interact with the plasma membrane as well as other proteins, thereby providing mechanosensory roles in the apical surface of hair cells of the inner ear (Muller and Grillet 2010).

To date, a total of less than 10 pathogenic LOXHD1 sequence variants have been reported to cause sensorineural nonsyndromic hearing loss, which include 7 truncating and 1 splicing variants (Human Gene Mutation Database). Individuals with causative sequence variants in the LOXHD1 gene have been associated with poor cochlear implant performance (Eppsteiner et al. 2012). Around 15 pathogenic missense sequence variants in the LOXHD1 gene have also been linked to late-onset Fuchs corneal dystrophy, a disorder that affects the corneal endothelium, often resulting in the need for corneal transplantation (Sundin et al. 2006).

The clinical sensitivity of this test has been reported to range up to 8%. For example, two independent investigations conducted in Japan indicated that pathogenic sequence variants in the LOXHD1 gene accounted for 0.3% (3/1,120 and 4/1,314) of nonsyndromic hearing loss cases (Nishio and Usame 2015; Mori et al. 2015). Disease-causing LOXHD1 variants were detected in 1.3% (2/160) of families from Turkey, Iran, Mexico, Ecuador, and Puerto Rico with autosomal recessive nonsyndrome deafness (Bademci et al. 2015). In a study involving Iranian consanguineous families with autosomal recessive nonsydromic hearing loss, 6.7% (2/30) harbored causative LOXHD1 sequence variants (Diaz-Horta et al. 2015). In another research investigation, disease-causing LOXHD1 sequence variants were detected in 8.3% (1/12) of families from Ital and Qatar with hearing impairment (Vozzi et al. 2014).

This test provides full coverage of all coding exons of the LOXHD1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.